Nociceptin, also known as Orphanin FQ, is a peptide of 17 amino acid residues that binds to the ORL-1 receptor and has the amino acid sequence:
SEQ ID NO: 1FGGFTGARKSARKLANQwhere the N-terminus (left hand side) is a free amine and the C-terminus (right hand side) is a free carboxylic acid.
ORL-1 is a GPCR having high sequence homology with other opioid receptors. Nociceptin and the ORL-1 receptor are widely distributed in the brain and central nervous system (CNS), as well as in the periphery. Among different roles including pain regulation, analgesia, tolerance and withdrawal, learning, memory, food intake, anxiety and mood, psychiatric disorders, motor function and locomotion, nociception, neuronal functions, cardiovascular and respiratory stress, and ill defined roles in inflammation, immunostimulation and immunity, have been attributed to nociceptin and the ORL-1 receptor.
Nociceptin(1-17) is composed of an N-terminal “message” tetrapeptide domain FGGF (amino acid residues 1-4) that activates the receptor, linked to a C-terminal “address” domain, (amino acid residues 7-17), that provides high affinity and selectivity for the receptor. The address domain of nociceptin contains key basic amino acid residues that likely bind acidic residues within the second extracellular loop of the ORL-1 receptor.
To date, no three-dimensional structure of the ORL-1 G protein-coupled receptor, either in complex with ligands or alone, is available. However, the solution structure of nociceptin has been investigated by CD and NMR spectroscopies, showing some helical structure from residues 4-17 under conditions that to some extent simulate a membrane environment (aqueous sodium dodecylsulphate (SDS) micelles) (Orsini et al., 2005, J. Biol. Chem. 280: 8134-8142). On the other hand, in water alone this peptide allows no discernible three dimensional structure by CD or NMR spectroscopy.
Nociceptin peptide analogues with ORL-1 receptor agonist or antagonist activity have potential therapeutic uses, and identification, of peptides having high binding affinity and functional activity as well as stability to proteolytic breakdown are required.